1) Field of the Invention
This invention relates to a process for producing a beta-lactam intermediate having desired chirality which is essential in carbapenem synthesis.
2) Brief Description of Disclosures in the Art
Carbapenem antibiotics, particularly thienamycin and imipenem (see U.S. Pat. Nos. 3,950,377 and 4,194,047) are well known for treating a broad spectrum of gram-negative and gram-positive bacterial infections.
Processes for synthesis of these type antibacterial agents are well known in the art as witness the following Patents issued inter alia to Merck & Co.; U.S. Pat. Nos. 4,543,257, 4,234,596, 4,360,684 and 4,232,030.
In order to develop, faster, less expensive and better methods for their production, research is continually being carried out in this area. One focus in this field has been on different modes for the synthesis of the starting azetidinone intermediate II, 3(S)-4(R)-3-[1(S)-hydroxyethyl]-4-(alkoxycarbonylmethyl)-azetidin-2-one.
One particular aspect is in the development of an efficient, convenient and inexpensive route to convert beta amino acid I, [2S-[2R*,(R*),3S*]]-3-amino-2-(1-hydroxyethyl)pentanedioic acid 5-methyl ester, (CAS Registry No. 79814-47-4), by suitable ring closure to beta lactam II, as seen by the following process sequence, ##STR1## The ring closure, i.e. cyclodehydration, of I to II, can be effected by using the prior art procedures of: H. Huang et al. in Chem. Letters, p. 1465 (1984) utilizing 2-chloro-1-methylpyridinium iodide; M. Ohno et al. in JACS, 103, p. 2406 (1981) using pyridine disulfide/triphenyl phosphine; D. Melillo et al. in Tet. Letters, p. 2783 (1980) and T. Kametani et al, in JACS, 102, p. 2060 (1980) using dicyclohexyldiimide; M. Ohno et al. in EPA Publication No. 0051234 (1982) using a heterocyclic disulfide, triphenylphosphine in the presence of an alkyl nitrile; and L. Biokofer et al, in Liebig's Ann. Chem., p.2195 (1975) using the Grignard reaction on the amino-ester. Earlier disclosures also include T. Mukaiyama et al. in Tet. Letters, 22. p. 1901-1904 (1970) which describe peptide synthesis utilizing 2,2'-pyridyldisulfide as an oxidant.
However, these reagents are very expensive especially when utilized on a plant scale.
A beta-lactam ring closure procedure has been reported by Y. Watanabe et al., Chem. Letters 1981, pp. 443-444, which employs a two phase liquid-liquid phase transfer system of methylene chloride/H.sub.2 O, tetrabutylammonium hydrogen sulfate as the phase transfer agent, and methanesulfonyl chloride, potassium bicarbonate as the ring closure agents. However, this system gives poor yields of II from I, primarily due to the instability of I in the basic aqueous phase.
What is desired is an improved process for the ring closure of I to II, which can be carried out efficiently on a large scale, eliminating the use of expensive reagents and aqueous phase systems, to obtain high yields of product II.